Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31

Philomena Mburu; Mirna Mustapha; Anabel Varela; Dominique Weil; Aziz El-Amraoui; Ralph H. Holme; Andreas Rump; Rachel E. Hardisty; Stéphane Blanchard; Roney S. Coimbra; Isabelle Perfettini; Nick Parkinson; Ann Marie Mallon; Pete Glenister; Mike J. Rogers; Adam J. Paige; Lee Moir; Jo Clay; Andre Rosenthal; Xue Zhong Liu; Gonzalo Blanco; Karen P. Steel; Christine Petit; Steve D.M. Brown

doi:10.1038/ng1208

Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31

Philomena Mburu, Mirna Mustapha, Anabel Varela, Dominique Weil, Aziz El-Amraoui, Ralph H. Holme, Andreas Rump, Rachel E. Hardisty, Stéphane Blanchard, Roney S. Coimbra, Isabelle Perfettini, Nick Parkinson, Ann Marie Mallon, Pete Glenister, Mike J. Rogers, Adam J. Paige, Lee Moir, Jo Clay, Andre Rosenthal, Xue Zhong LiuGonzalo Blanco, Karen P. Steel, Christine Petit, Steve D.M. Brown

Otolaryngology

Research output: Contribution to journal › Article › peer-review

227 Scopus citations

Abstract

The whirler mouse mutant (wi) does not respond to sound stimuli, and detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicates that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells (IHCs) and outer hair cells (OHCs). BAC-mediated transgene correction of the mouse phenotype and mutation analysis identified the causative gene as encoding a novel PDZ protein called whirlin. The gene encoding whirlin also underlies the human autosomal recessive deafness locus DFNB31. In the mouse cochlea, whirlin is expressed in the sensory IHC and OHC stereocilia. Our findings suggest that this novel PDZ domain-containing molecule acts as an organizer of submembranous molecular complexes that control the coordinated actin polymerization and membrane growth of stereocilia.

Original language	English (US)
Pages (from-to)	421-428
Number of pages	8
Journal	Nature genetics
Volume	34
Issue number	4
DOIs	https://doi.org/10.1038/ng1208
State	Published - Aug 1 2003

ASJC Scopus subject areas

Genetics

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10.1038/ng1208

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Mburu, P., Mustapha, M., Varela, A., Weil, D., El-Amraoui, A., Holme, R. H., Rump, A., Hardisty, R. E., Blanchard, S., Coimbra, R. S., Perfettini, I., Parkinson, N., Mallon, A. M., Glenister, P., Rogers, M. J., Paige, A. J., Moir, L., Clay, J., Rosenthal, A., ... Brown, S. D. M. (2003). Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nature genetics, 34(4), 421-428. https://doi.org/10.1038/ng1208

Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. / Mburu, Philomena; Mustapha, Mirna; Varela, Anabel; Weil, Dominique; El-Amraoui, Aziz; Holme, Ralph H.; Rump, Andreas; Hardisty, Rachel E.; Blanchard, Stéphane; Coimbra, Roney S.; Perfettini, Isabelle; Parkinson, Nick; Mallon, Ann Marie; Glenister, Pete; Rogers, Mike J.; Paige, Adam J.; Moir, Lee; Clay, Jo; Rosenthal, Andre; Liu, Xue Zhong; Blanco, Gonzalo; Steel, Karen P.; Petit, Christine; Brown, Steve D.M.

In: Nature genetics, Vol. 34, No. 4, 01.08.2003, p. 421-428.

Research output: Contribution to journal › Article › peer-review

Mburu, P, Mustapha, M, Varela, A, Weil, D, El-Amraoui, A, Holme, RH, Rump, A, Hardisty, RE, Blanchard, S, Coimbra, RS, Perfettini, I, Parkinson, N, Mallon, AM, Glenister, P, Rogers, MJ, Paige, AJ, Moir, L, Clay, J, Rosenthal, A, Liu, XZ, Blanco, G, Steel, KP, Petit, C & Brown, SDM 2003, 'Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31', Nature genetics, vol. 34, no. 4, pp. 421-428. https://doi.org/10.1038/ng1208

Mburu, Philomena ; Mustapha, Mirna ; Varela, Anabel ; Weil, Dominique ; El-Amraoui, Aziz ; Holme, Ralph H. ; Rump, Andreas ; Hardisty, Rachel E. ; Blanchard, Stéphane ; Coimbra, Roney S. ; Perfettini, Isabelle ; Parkinson, Nick ; Mallon, Ann Marie ; Glenister, Pete ; Rogers, Mike J. ; Paige, Adam J. ; Moir, Lee ; Clay, Jo ; Rosenthal, Andre ; Liu, Xue Zhong ; Blanco, Gonzalo ; Steel, Karen P. ; Petit, Christine ; Brown, Steve D.M. / Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. In: Nature genetics. 2003 ; Vol. 34, No. 4. pp. 421-428.

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abstract = "The whirler mouse mutant (wi) does not respond to sound stimuli, and detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicates that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells (IHCs) and outer hair cells (OHCs). BAC-mediated transgene correction of the mouse phenotype and mutation analysis identified the causative gene as encoding a novel PDZ protein called whirlin. The gene encoding whirlin also underlies the human autosomal recessive deafness locus DFNB31. In the mouse cochlea, whirlin is expressed in the sensory IHC and OHC stereocilia. Our findings suggest that this novel PDZ domain-containing molecule acts as an organizer of submembranous molecular complexes that control the coordinated actin polymerization and membrane growth of stereocilia.",

author = "Philomena Mburu and Mirna Mustapha and Anabel Varela and Dominique Weil and Aziz El-Amraoui and Holme, {Ralph H.} and Andreas Rump and Hardisty, {Rachel E.} and St{\'e}phane Blanchard and Coimbra, {Roney S.} and Isabelle Perfettini and Nick Parkinson and Mallon, {Ann Marie} and Pete Glenister and Rogers, {Mike J.} and Paige, {Adam J.} and Lee Moir and Jo Clay and Andre Rosenthal and Liu, {Xue Zhong} and Gonzalo Blanco and Steel, {Karen P.} and Christine Petit and Brown, {Steve D.M.}",

note = "Funding Information: We thank J. Hardelin, J. Levilliers and S. Cure for critical reading of the manuscript. The confocal microscope was purchased with a donation from Marcel and Liliane Pollack. This work was supported by the Medical Research Council, Defeating Deafness, a grant from the European Community, the Foundation Srittmatter (Retina France) and the US National Institutes of Health.",

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AU - Weil, Dominique

AU - El-Amraoui, Aziz

AU - Holme, Ralph H.

AU - Rump, Andreas

AU - Hardisty, Rachel E.

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AU - Perfettini, Isabelle

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AU - Mallon, Ann Marie

AU - Glenister, Pete

AU - Rogers, Mike J.

AU - Paige, Adam J.

AU - Moir, Lee

AU - Clay, Jo

AU - Rosenthal, Andre

AU - Liu, Xue Zhong

AU - Blanco, Gonzalo

AU - Steel, Karen P.

AU - Petit, Christine

AU - Brown, Steve D.M.

N1 - Funding Information: We thank J. Hardelin, J. Levilliers and S. Cure for critical reading of the manuscript. The confocal microscope was purchased with a donation from Marcel and Liliane Pollack. This work was supported by the Medical Research Council, Defeating Deafness, a grant from the European Community, the Foundation Srittmatter (Retina France) and the US National Institutes of Health.

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